CA2723435A1 - Novel depigmenting compositions in the form of a petroleum jelly-free and elastomer-free anhydrous composition comprising a solubilized phenolic derivative and a retinoid - Google Patents

Abstract

The present invention relates to a new depigmenting composition, in particular for topical application, comprising, as pharmaceutical active ingredients, a solubilized phenol derivative and a retinoid, in the form of an anhydrous composition without petroleum jelly and without elastomer, its preparation process and its use in dermatology.

Description

New depigmenting compositions in the form of a composition anhydrous without petrolatum and without elastomer comprising a phenol derivative solubilized and a retinoid.

The present invention relates to a new depigmenting composition cosmetic or pharmaceutical form of anhydrous ointment not containing petrolatum and without elastomer, especially for topical application, comprising as pharmaceutical active ingredients a solubilized phenolic derivative and a retinoid.

Among the therapeutic agents recommended in the treatment of hyperpigmentation dermal, phenolic derivatives and more particularly polyphenols remain for decades, among the most effective assets. Use Therapeutic these agents result from the observation of cutaneous depigmentations in workers of the rubber industry where some of these products are used as antioxidants.
Since then, many studies have only confirmed their effectiveness alone or Related to other depigmentants [Jorge L. Sanchez, MD and Miguel Vazquez, MD
International Journal of Dermatology Jan-Feb 1982 vol 21 p55 58]. They appear as well as virtually unavoidable assets in the treatment of hyperpigmentation and are therefore present in many products commercial.

Among the phenolic derivatives, polyphenols such as hydroquinone are the assets most used pharmaceutical. Hydroquinone was the subject of the filing of various patent applications, and in particular US Pat. No. 3,856,934 where hydroquinone is combination with retinoic acid and a corticosteroid as a composition depigmentation.

Rucinol or lucinol, or 4-butyl-resorcinol is also an active ingredient pharmaceutical phenolic derivative, of the polyphenol type, marketed as agent brightening brown spots associated with pigmentation disorders (product Iklen).

But in the majority of cases, hydroquinone, rucinol or their salts or his derivatives are solubilized in the aqueous phase of the preparation.
It is known that a number of active ingredients having an activity therapeutics are sensitive to oxidation and are particularly affected by a

2 chemical degradation leading to a significant loss of their activity in presence of water.
Incorporation of a phenolic derivative such as hydroquinone or rucinol present therefore, in this type of aqueous preparation, a major disadvantage.
Indeed, the degradation of formulations containing derivatives phenolics such as hydroquinone or rucinol, alone or in combination with others active subtances. These assets are actually known for their great sensitivity to the oxidation and heat causing a decrease in efficiency, a browning rapid formulations and sometimes even a semixtion of the formulation.
In addition, to accelerate their solubilization, phenol derivatives such as hydroquinone or rucinol, are often exposed to heat during phase of production of the composition, in particular in conventional emulsions, phenomenon which initiates and accelerates the phenomenon of browning.

In the prior art, reducing agents are used to combat this degradation, in particular sulphites, almost unavoidable. However, these antioxidants have a number of disadvantages such as problems skin irritation, odor in formulations or destabilization of the formula related to a loss of viscosity.
Another disadvantage due to the presence of phenolic derivatives such as hydroquinone alone or in combination with other active agents in the composition, is their strong irritating power.

Hydroquinone because of its high concentration of irritating generate post-inflammatory hypermelanosis and ochronosis phenomena.

Local irritation and dermatitis may develop after a use prolonged hydroquinone at high concentration [N-acetyl4S cysteaminylphenol as a new type of depigmenting agent Jimbow K. Arch. Dermatol. 1991 Oct; 127 (10): 1528-1534].

Treatment with hydroquinone may be accompanied by irritation that may drive to post-inflammatory hyperpigmentation. The incidence of irritation depends of the

3 hydroquinone concentration. The latter is important enough for 10% concentration and decreases sharply for preparations dosed at 5% and would be virtually zero at the concentration of 2%
depigmentation JP. Ortonne Ann. Dermatol. Venerol.1986, 113: 733-736].

The chosen galenic can therefore play a leading role in the minimization of these effects.

Therefore, derivative pharmaceutical assets should be formulated phenolics and in particular hydroquinone or rucinol in the form of solubilized in a formulation to avoid the presence of sulphites and / or to remove or limit the use of antioxidants.

For ease of use and even more so in the case of a combination with a dispersed retinoid, it is important that an anhydrous composition without Vaseline and without elastomer, however, has a sufficiently high viscosity.

Anhydrous compositions currently available on the market, or such than described in application US2006 / 0120979 and allowing the formulation of principles water-sensitive active ingredients, while ensuring good chemical stability, are generally ointment-type compositions consisting mainly of petroleum jelly or, in more recent formulations, on the one hand elastomer.
The use of petrolatum is not satisfactory for the reasons following:
after application, certain compositions comprising petroleum jelly are felt as sticky and fat, and are more brilliant;
- Moreover, the preparation of compositions in the form of ointments based Vaseline requires special compounds and conditions. In indeed, vaseline is solid at room temperature, and has a melting point than 40 C. In order to be able to mix it with other compounds, it is necessary to formulate it in the liquid state, and thus to make the compositions at temperatures above 40 C. However, such The process has the disadvantage of forming a crusting phenomenon. In effect, the faster cooling of the outside of the composition by relationship to its heart causes its abnormal hardening (crusting), which

4 has the effect of slowing down or even preventing the realization of a perfect homogenization;
- finally, the formulation of phenolic derivatives, in particular hydroquinone or rucinol, is delicate because of the sensitivity of these assets to the heat.
The use of elastomer in a relatively large quantity makes it possible to give a certain viscosity to anhydrous formulations (US2006 / 0120979 patent) without the disadvantages of Vaseline. However, in the present invention, his use is not satisfactory for the following reasons:
proportion elastomer present in these formulations prevents the incorporation of of sufficient quantities of oily and waxy compounds with the advantage of to give the preparation the desired emollient properties.

One of the aims of the present invention is to propose a composition anhydrous pharmaceutical product without vaseline and elastomer, intended for application topical, which has a viscosity equivalent to that of ointments containing petrolatum, which is easy to prepare, which ensures a good chemical stability of the assets and in which certain volatile compounds can be used. The composition according to the invention has in particular these advantages thanks to its method of preparation.
The invention therefore also relates to the preparation process particularly advantage of such a composition, in which the step of incorporating the assets is performed at room temperature. The desired viscosity of the composition according to the invention is obtained with the aid in particular of the choice of the fatty substances used.
The absence elastomer makes it possible to obtain the desired particularity of the formulation, know, a certain fluidity of the composition at the end of manufacture incorporation easy at room temperature and a perfect homogenization of the assets then a final viscosity reached about 24 hours after manufacture.

Another object of the present invention is to propose a composition anhydrous pharmaceutical product without vaseline and elastomer for application topical with prolonged stability, allowing release optimized assets while being very well tolerated.

The present invention thus relates to a new stable composition under form of anhydrous composition not containing petroleum jelly and without elastomer, in particular for topical application, including, as active ingredients pharmaceutical, WO 2009/15667

5 PCT / FR2009 / 051036 a phenol derivative of the solubilized polyphenol type and a retinoid. The composition Anhydrous anhydride according to the present invention also has both excellent stability and safety.
By elastomer according to the invention is meant polyorganosiloxane elastomer.

By anhydrous composition is meant a composition comprising a quantity of water less than or equal to 5% by weight relative to the total weight of the composition.
In a preferred embodiment according to the invention the composition does not contain water.
By stable composition is meant a chemically stable composition and physically.
By chemical stability is meant in particular that no degradation of the active is observed over time and at temperatures between 4 and 40 C. By stability physical, it is understood that the compositions do not exhibit a fall of viscosity over time and at temperatures between 4 and 40 C.

The object of the present invention is thus a pharmaceutical composition anhydrous, characterized in that it comprises:

at. at least one first phenolic derivative pharmaceutical active agent, b. at least one second pharmaceutical active agent of the retinoid type, vs. glyceryl behenate, its derivatives or their mixtures, d. at least one solvent of the phenolic derivative, said composition containing neither petroleum jelly nor elastomer polyorganosiloxane.

The anhydrous composition according to the invention can be presented under the different known galenic forms that the person skilled in the art will adapt to the use particular of the composition.
The compositions according to the invention are preferably formulated for a application topically.

Topically, we mean an external application on the skin or mucous membranes.

The compositions according to the invention can be presented under all the forms galenics normally used for topical administration. AT
title non-limiting example of the compositions as described in the pharmacopoeias

6 (USP32-NF27 - Chap <1151> - Pharmaceutical Dosage Forms) or (Edition 6.3 - Chapter Semi-solid preparations for application cutaneous or as defined in the decision trees of the Food and Drug United States Administration (CDER) Data Standards Manual Definitions for topical Dosage Forms). The compositions according to the invention can therefore be presented under liquid, semi-solid, pasty or solid form and, more particularly, under form ointments, oily solutions, lotion-type dispersions eventually biphasic, serum, anhydrous or lipophilic gels, powders, buffers soaked, of syndets, wipes, sprays, mousses, sticks, shampoos, compresses, washing bases, emulsions of liquid or semi-liquid from type oil in glycol or glycol in oil, a microemulsion, suspensions or semi-liquid or solid emulsions of the white or colored cream type, emulsions multiple or reverse, gel or ointment, suspensions of microspheres or nanospheres or of lipid or polymeric vesicles, or microcapsules, micro- or nanoparticles or polymeric or gelled patches for controlled release.

The anhydrous composition according to the invention is preferably an ointment. By ointment according to the invention, is meant a composition such as defined in the American or European pharmacopoeias mentioned above. FDA
defines thus the ointment as a semi-solid composition comprising, as vehicle, less than 20% of water and volatile compounds and more than 50% of hydrocarbons, waxes, or polyol. In some cases, when volatile levels are important such compositions may be called creams (Decision tree of the Food and American Drug Administration (FDA)). The American Pharmacopoeia defines a ointment as a product whose base is a vehicle that may belong to the 4 following classes: hydrocarbon base or absorbent base or washable base water or base soluble in water. In the present invention, the ointment as defined to the American pharmacopoeia, is of hydrocarbon base type. The Pharmacopoeia European defines ointment as a monophase composition in which can be dispersed liquids or solids.

Preferably, the ointment according to the invention is a composition thick to ambient temperature, which comprises between 80 and 98% by weight with respect to weight total of the composition of hydrophobic compounds distinct from petrolatum. Of such compounds are chosen in particular from liquid oils alone or in mixed,

7 said oils may be hydrocarbons, esters, oils vegetable and / or silicone oils, volatile or non-volatile, which can be gelled by compounds solid lipophilic materials at room temperature, such as waxes, butters, esters of fatty acids.
Optionally, a measurement of the flow threshold can be carried out in order to characterize the finished product.
For the measurement of the flow threshold, a HAAKE rheometer of type VT550 with a Mobile measurement SVDIN was used.
The rheograms are carried out at 25 ° C. and at an imposed speed of 0 to 100s -1. The Viscosity values are given at shear values of 4 s- ', 20s-1, 100s- ' (Y). By flow threshold (io expressed in Pascal) is meant the force necessary (minimum shear stress) to overcome the cohesive forces of type Van der Waals and cause the flow.

Throughout the present application, ambient temperature means a temperature between 20 and 30 C.

The anhydrous nature of the ointment does not contain petrolatum or elastomer according to the invention makes it possible to avoid instability of the phenolic derivative by particular sound oxidation in an aqueous medium. In such a formulation the use antioxidants sulphites essential for the stabilization of hydroquinone in medium aqueous is no longer necessary. Therefore, in a preferred mode according to the invention, the composition does not contain sulphites and contains a quantity antioxidants less than 0.3% by weight relative to the total weight of the composition, of preferably less than 0.2%. Antioxidants that can be used according to the invention are preferentially antioxidants such as vitamin E and its derivatives, like the DL
alpha Tocopherol or Roche tocopherol acetate; vitamin C and its derivatives, such as Ascorbyl Rock Palmitate, butylhydroxytoluene sold under the name of Nipanox BHT by Clariant.

Thus, the anhydrous ointment according to the invention comprises at least one first phenolic derivative pharmaceutical active agent solubilized at least one first retinoid-type pharmaceutical active agent, glyceryl behenate and / or derivatives and / or their mixtures,

8 optionally, at least one lipophilic thickener or gelling agent additional, at least one solvent of the phenolic derivative, optionally, at least one solvent or dispersant of the retinoid, and optionally at least one fatty substance or oil.

Preferably, as mentioned above, the anhydrous composition according to the invention contains substantially no petrolatum, ie not more than 1% by weight of Vaseline relative to the total weight of the composition.
By phenolic derivative pharmaceutical active agent, mention may be made limiting polyphenols and more particularly hydroquinone, 4-hydroxyanisol, monoethyl hydroquinone ether, hydroquinone monobenzyl ether and rucinol or lucinol and his salts,.

By salts of rucinol is meant in particular salts formed with a base pharmaceutically acceptable, especially a mineral base such as sodium hydroxide, the potash and ammonia or an organic base such as lysine, arginine, the N-methyl-glucamine, but also the salts formed with fatty amines as dioctylamine, aminomethyl propanol and stearylamine.

Preferably, hydroquinone or rucinol is used.

Advantageously, the amount of pharmaceutical active derivative type phenolic is from 0.01 to 10% by weight relative to the total weight of the composition, from preference from 0.05 to 6% by weight and more particularly from 0.1 to 5% by weight.
According to the invention, the composition comprises as second active pharmaceutical, a retinoid.
By retinoid is meant any compound binding to receptors (receptors retinoic acid (RARs) and / or retinoic X receptors (RXRs)) as well as their precursors and derivatives.
Retinoids that can be used in the context of the invention include including all-trans retinoic acid or tretinoin, 13-cis-acid retinoic or isotretinoin, acitretin, arotinoic acid, retinol, tazarotene, retinaldehyde, etretinate and the protected compounds in EP 0 199 patent applications 636, US
4,666,941, US 4,581,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348,

9 EP0325540, EP0359621, EP0409728, EP0409740, EP0552282, EP0584 191, EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658 553, EP

679 628, EP 0 679 631, EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928, EP
0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EP 0 776 881, EP 0 823 903, EP0832057, EP0832081, EP0816352, EP0826657, EP0874626, EP0934 295, EP 0 915 823, EP 0 882 033, EP 0 850 909, EP 0 879 814, EP 0 952 974, EP

905 118, EP 0 947 496, WO98 / 56783, WO99 / 10322, WO99 / 50239, WO99 / 65872, WO2006 / 066978, and in particular 6- (3- (1-adamantyl) -4-methoxyphenyl) -2-naphthoic acid (adapalene) and its methyl ester, the compounds protected in the Patent Application WO2006 / 066978 such as 3 "-tert-butyl-4 '- (2-hydroxy) ethoxy) -4 "-Pyrrolidin-1-yl- [1,1 ', 3', 1"] terphenyl-4-carboxylic acid, the compounds of request patent WO2007066041 including 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro) 5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid or one of its enantiomers, compounds of patent application WO 05/56516, including 4 '- (4-isopropylamino) butoxy) -3 '- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) biphenyl-4-carboxylic acid, the compounds of the patent application WO2005056510 of which the acid {3-hydrooxy-3- [4- (2-ethoxyethoxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -prop-1-ynyl} -benzoic, the compounds of the patent application WO2005037772 of which 4- [2- (3-tert-butyl-4-diethylamino-phenyl) -2-hydroxyimino-ethoxy] -2-hydroxy benzoic.

In particular, adapalene and its salts, and the acid 3 "- will be preferred.
tert-butyl 4 '- (2-hydroxy-ethoxy) -4 "-pyrrolidin-1-yl- [1,1', 3 ', 1"] terphenyl-4-carboxylic acid.

By salts of adapalene is meant in particular salts formed with a base pharmaceutically acceptable, especially inorganic bases such as welded, potash and ammonia or organic bases such as lysine, arginine, N-methylglucamine, and salts formed with fatty amines such as dioctylamine and stearylamine.
Retinoid precursors means their biological precursors immediate or substrates, as well as their chemical precursors.
Derivatives of retinoids include both their metabolic derivatives than their chemical derivatives.

Preferably, the composition comprises a quantity of retinoid agent included between 0.0001 and 1% by weight relative to the total weight of the composition, preference between 0.001 and 0.5%, even more preferably between 0.01 and 0.3 % in weight.

The composition according to the invention comprises glyceryl behenate, its derivatives Or mixtures thereof. By derivatives of glyceryl behenate is meant in particular But not exclusively glyceryl monobhenate, glyceryl dibenenate, tribehenin. The composition according to the invention comprises in particular preferred, the a mixture of glyceryl dibenenate, tribehenin and behenate glyceryl. Such In particular, the mixture is marketed under the name Compritol 888 by

10 Gattefossé. In the remainder of the description of the invention, behenate glyceryl, means glyceryl behenate, its derivatives or mixtures thereof. Behenate Glycerol is an oily phase thickener. In the composition according to the invention, the glyceryl behenate becomes en masse in time and allows to prepare a hydrophobic composition whose final viscosity is obtained only after one certain time. In the particular case according to the invention, the constituents and the process are actually chosen so as to impart fluidity to the composition at the end of immediate manufacturing, facilitating the homogenisation of the different constituents but a final viscosity sought about 24 hours after manufacture. For get this As a result, the composition comprises from 1 to 40%, preferably from 5 to 30%, and even more preferably from 10 to 25% by weight relative to the total weight of the composition of glyceryl behenate.

The composition according to the invention may also comprise at least one gelling lipophilic, or else called lipophilic thickener, additional. Such gelling agent, or additional lipophilic thickener provides better physical stability to the composition, in particular where the latter is subject to temperatures of accelerated conditions of stability (ICH criteria) around 40 C.
effect, these compounds are used in the present invention as adjusters of viscosity: in In particular, by choosing them judiciously, they ensure the stability of the composition at 40 C. This therefore gives a better stability to the compositions obtained.
By additional lipophilic thickeners or gelling agents according to the invention, we hear compounds distinct from glyceryl behenate, chosen in particular from waxes, fatty alcohols, hydrogenated oils, fatty acid esters.

11 By wax is generally meant a lipophilic compound, which is ambient temperature (25 C), solid state change / reversible liquid, having a melting point greater than or equal to 30 C up to 200 C and especially up to 120 ° C. As useful waxes, mention may be made of carnauba wax, the waxes microcrystallines, beeswax, marketed under the name of Cerabeil white by Barlocher, or candellila wax.
As usable fatty alcohols, mention may be made of oleic alcohol, alcohol cetyl, cetearyl alcohol or stearyl alcohol.
By hydrogenated oil is meant oils obtained by hydrogenation catalytic of animal or vegetable oils having fatty chains, linear or branched, C8-C32. Among these, there may be mentioned the oil of jojoba hydrogenated isomeric jojoba oil such as jojoba oil partially isomerized hydrogenated trans manufactured or marketed by the company Desert Whale under the trade reference ISO-JOJOBA-50, hydrogenated sunflower oil, hydrogenated castor oil, sold in particular under the name of Cutina HR
by Cognis, hydrogenated coconut oil and hydrogenated lanolin oil; of preference, Hydrogenated castor oil will be used.
As fatty acid esters that may be used, mention may be made of lanolin sold especially under the name Medilan by Croda, glyceryl esters of fatty acids sold under the name of Gelucire by Gattefossé, hydrogenated glycerides of coconut sold under the name of Akosoft 36 by Karlshamns, or the monostearate of diethylene glycol or propylene glycol sold respectively under the name of Hydrine or of Monosteol by Gattefossé.

Thus, preferably, the composition comprises a global amount of behenate glyceryl and optionally lipophilic thickeners or gelling agents additional between 1 and 40% by weight relative to the total weight of the composition, of preferably between 5 and 35%. Preferably, the composition comprises 10 to 25% by weight of glyceryl behenate, and from 0 to 30% by weight of thickener lipophilic additional, preferably 1 to 10%.

By composition without elastomer according to the invention is meant a composition anhydrous composition comprising at most 1% by weight of elastomer relative to the total weight of the composition. Preferably, as mentioned above, the ointment the invention contains no elastomer.

12 By elastomer is meant any polyorganosiloxane elastomer, namely any polymer chemically crosslinked siloxane having viscoelastic properties.
Indeed, the desired viscosity of the composition according to the invention is obtained at ugly in particular glyceryl behenate and the choice of other fatty substances used.
The absence of elastomer within the composition makes it possible, in particular, to introduce more of oily compounds thus conferring on the composition the properties emollient sought. The absence of elastomer makes it possible in particular to obtain the effect of glyceryl behenate more marked, namely, a fluidity of the composition at the end of manufacture and a final viscosity reached about 24 hours after manufacture.
The composition also comprises at least one solvent of the active pharmaceutical phenolic derivative. As a solvent for the phenolic derivative, hears especially solvents of alcoholic or glycolic type.
By alcoholic type solvent according to the invention, there may be mentioned for example the Aliphatic, linear or branched alcohols, such as anhydrous or non-ethanol anhydrous, isopropanol, butanol. The composition according to the invention contains preferentially ethanol.
By glycolic type solvent according to the invention, there may be mentioned for example the propylene glycol, ethylene glycol, 1,3-butylene glycol and dipropylene glycol. The solvents of the phenolic derivative of alcoholic or glycolic type preferred according to the invention include ethanol and propylene glycol.
According to one of the preferred modes according to the invention, the solvent of the active pharmaceutical phenolic derivative is ethanol.
Preferably, the total amount of solvent is between 1 and 80% by weight, preferably between 5 and 50% and more particularly between 10 and 30% by weight.
weight, by relative to the total weight of the composition.

The composition also comprises at least one solvent or dispersant retinoid. The solvent or dispersant of the retinoid may be oily type, alcoholic or glycolic. The alcoholic or glycolic solvents can be of the type of those described above. The oily solvents or dispersants can be of any known type of those skilled in the art, in particular mineral oils, vegetable oils, esters or triglycerides.
According to one of the preferred modes according to the invention, the preferred retinoid is adapalene and is therefore present in dispersed form. The preferred dispersant of adapalene according to the invention is preferably of the oily type, and more particularly of the

13 triglycerides such as Caprylic / Capric Triglycerides sold under the name of Miglyol 812 N by IMCD or glycolic type, such as propylene glycol.
Preferably, the total amount of solvent or dispersant of the retinoid is between 1 and 80% by weight, and preferably between 1 and 60% by weight.
weight, by relative to the total weight of the composition.

In addition to the alcoholic or glycolic solvent, and in order to prepare a composition having the desired properties, for example in consistency, in texture or for their qualities emollient or moisturizing agents, those skilled in the art can add one or more fat or oil selected from the following list:
vegetable oils, such as sweet almond oil sold by Sictia or oil of sesame sold by CPF, silicone oils such as cyclomethicone sold under the name ST-Cyclomethicone 5NF by Dow Corning or Dimethicone sold as Q7 9120 silicon fluid by Dow Corning, mineral oils, such as Marcol 152 or Primol 352 sold by Esso, perhydrosqualene, triglycerides such as caprylic / capric triglycerides sold under the name Miglyol 812 N by IMCD, or derivatives such as PEG-8 caprylic capric triglycerides sold under the name of LABRASOL by the company Gattefossé, esters, such as Octyl Dodecyl Myristate sold under the name MOD by Gattefossé, the C12-C15 alkyl benzoate sold under the name Tegosoft TN by Goldschmit or Cetearyl Isononanoate sold under the name Cetiol SN PH
by Cognis Guerbet alcohols such as octyldodecanol sold under the name Eutanol G
by Cognis ethers and derivatives, such as PPG-15 stearyl ether sold under the name of Arlamol E
by Croda, - and their mixtures.

When at least one fatty substance or oil is present in the composition, their amount is between 0.05 and 98% by weight, preferably between 1 and 80%
in weight.

14 Optionally, the composition according to the invention may also comprise minus one surfactant, and / or at least one binder.

The surfactants used are preferably nonionic surfactants, used for example, but not exclusively, to facilitate the incorporation of some components such as glycols in the oily phase of the composition.
Among the surfactants that may be used according to the invention, mention may be made of esters of glyceryl and polyethylene glycol, such as the stearate mixture of glyceryl and PEG-100 stearate, sold under the name Arlacel 165 by Uniqema, the mixture of glyceryl stearate and PEG-75 stearate, sold under the name Gelot 64 by Gattefossé, the glyceryl stearate sold under the name Cutina GMSV by Cognis;
emulsifying waxes, such as self-emulsifying wax sold under the name of Polawax NF by Croda, or PEG-8 beeswax sold as Apifil by Gattefossé; polysorbate 80 sold under the name Tween 80 by Uniqema;
oil of ricin and derivatives such as BASF polyoxyethylenated castor oil sold under the trade name of Cremophor EL or the mixture of stearate of glycerol and PEG-2 stearate, sold under the name Sedefos 75 by Gattefossé.
The amount of surfactants is between 1 and 20% by weight, preferably between 1 and 10% by weight.

The composition may also comprise at least one binder. Among the binders which may be mentioned are magnesium stearate sold by Brenntag, starch corn sold by Roquette, talc sold by WCD, cholesterol sold by Croda or the silica sold by Degussa.
The binders can be used in an amount of between 1 and 30% by weight, of preferably between 1 and 20% by weight.

The composition according to the invention may also contain additives between 0 and 20%, preferably between 0 and 10% by weight relative to the total weight of the composition, additives that one skilled in the art will choose according to the desired effect.
Among the additives, for example, taken alone or in combination vitamins such as vitamin PP or niacinamide, soothing and / or anti-irritant agents such as PPG-12 / SMDI copolymer Sold by Bertek pharmaceuticals under the trade name Polyolprepolymer-2 or still glycyrrhetinic acid or its derivatives as for example Enoxolone sold by the company Cognis, or hyaluronic acid, moisturizing or humectant agents: mention may be made, for example, of sugars and derivatives, glycols, glycerin, sorbitol, 5 - lecitins, cholesterol, preservatives, such as paraben methyl sold under the name Nipagin M by Clariant, the propyl paraben sold under the name of Nipasol by Clariant, or still the phenoxyethanol sold under the name of phenoxetol by Clariant, acids or bases such as citric acid, sodium citrate, triethanolamine, Aminomethylpropanol, sodium hydroxide, diisopropanolamine, other additives which make it possible to confer on the said preparation properties specific.
Preferably, the composition according to the invention comprises, by weight per report to

15 total weight:
- 0.01 to 10% of at least one derivative pharmaceutical phenolic, - 0.0001 to 1% of at least one pharmaceutical active ingredient retinoid, - 1 to 40% of glyceryl behenate, 1 to 80% of at least one ethanolic or glycolic solvent, 0 to 30% additional lipophilic thickeners, - 0.05 to 98% of a fatty substance or additional oil, 0 to 20% of additives.
More preferentially, the composition according to the invention comprises, by weight by ratio to the total weight:
- 0.01 to 10% of at least one phenolic derivative, of type polyphenol ,, 0.0001 to 1% of a retinoid, preferably adapalene, - 5 to 30% of glyceryl behenate, 5 to 50% of at least one ethanolic or glycolic solvent, 1 to 10% additional lipophilic thickeners, - 1 to 80% of oil (s), 0 to 20% of surfactants, 0 to 30% of a binder (s),

16 - 0 to 10% of additives Even more preferentially, the composition according to the invention comprises, in weight per ratio to the total weight:
- 0.01 to 5% hydroquinone or rucinol, 0.01 to 0.3% of adapalene, - 10 to 25% of glyceryl behenate, 10 to 30% of ethanol, 1 to 10% additional lipophilic thickeners, - 1 to 80% of oils, 0 to 10% of surfactants, 0 to 20% of binder (s), 0 to 10% of additives.

The subject of the invention is also the use of the composition obtained as a medicine.

More particularly, the composition can be used to prepare a drug for the treatment and prevention of disorders hyperpigmentation such as melasma, chloasma, lentigines, senile lentigo, vitiligo, the spots freckles, post-inflammatory hyperpigmentations due to abrasion, a burn, scar, dermatitis, contact allergy; the nevi, the hyperpigmentations with genetic determinism, the original hyperpigmentation metabolic or drug, melanoma or any other lesions hyperpigmentation.

The subject of the invention is also the use of the composition in the field cosmetic.

The compositions according to the invention also find an application in the field cosmetics, in particular in the protection against the harmful aspects of sun, for prevent and / or fight against photo-induced aging or chronological of the skin and integuments.

The invention also relates to a non-cosmetic cosmetic treatment method therapeutic beautifying the skin and / or improving its surface appearance, characterized

17 in that a composition is applied to the skin and / or its integuments comprising adapalene and at least one depigmenting agent.

Finally, the present invention also relates to a preparation process compositions according to the invention. Such a method makes it possible in particular retention compounds in the fluid state at the end of manufacture. One of the characteristics of the process for preparing the compositions according to the invention being the incorporation of the active phase at room temperature, that is to say that step Final mixing phase is carried out at room temperature.
By ambient temperature is meant a temperature of between 20 and 30 vs.
In the process according to the invention, by active phase is meant a phase containing at least one active ingredient. Similarly, in the process according to the invention, phase not active means a phase consisting of any other different ingredient of active ingredient. In the composition according to the invention the non-active phase is preferably an oily phase containing at least glyceryl behenate, of preferably with another oily compound as described above.

Advantageously, the process for producing the composition according to the invention is according to Example 1, characterized in that the phases containing the assets Pharmaceuticals are mixed at room temperature.

The process thus gives the product the following advantages - Good homogeneity of the assets because all the components are mixed within a fluid phase.
- The absence of crusting phenomenon during cooling and a good fluidity of the product until the end of manufacture.
- Easy packaging due to the low viscosity at the end of manufacture, the viscosity end of the ointment-type composition not being immediately end of production.
- The mixture of the active and non-active phases at ambient temperature avoids the volatilization of the solvent (s) and the degradation of the assets, potentially sensitive to heat, especially phenolic derivatives such as hydroquinone or rucinol.

18 The sample formulations below illustrate the compositions according to the invention, without however limiting the scope thereof. The quantities of constituents are expressed in% by weight relative to the total weight of the composition.

Example 1: Preparation Process of the Compositions a) Preparation of the fat phase or non-active phase (phase A):

In the beaker of manufacture, introduce all the constituents:
consistency and oils. Stir with heat to obtain a fusion homogeneous ingredients. Stop the heating.
Add the fatty phase additives if necessary, then cool to temperature ambient with stirring.

b) Active phase:

Solubilize the phenolic derivative drug, in the appropriate solvent, add antioxidant (s) if necessary, and shake until the solubilization the asset. (phase VS) Solubilize the retinoid in the appropriate solvent. (phase B) If presence of a retinoid dispersed in the composition, for example adapalene, weigh at this stage, adapalene in an oily liquid, and disperse under strong shear (phase B).
c) Realization of the final composition:

Incorporate, with agitation, the active phase (s) at the base form at ambient temperature, for solubilizations in the ethanolic phase or glycolic.
Incorporate additional phases as needed.

Homogenize and continue cooling with stirring.

Packaging is done at the end of the production process because the product does not have still his final viscosity.

19 For all formulations, physical stability is measured by a observation macroscopic and microscopic formulation at room temperature, at 4 C
and 40 C after 1 month, 2 months and optionally 3 months and 6 months of storage.
Macroscopic observation makes it possible to guarantee the physical integrity of products and microscopic observation makes it possible to check that there is no recrystallization of assets solubilized.
Chemical stability is measured by assaying the assets by external calibration in HPLC and the results are expressed as% recovery from the value obtained at TO or in relation to the theoretical title.

Example 2: Composition 2 Phases INCI name% form A Glyceryl behenate 16.00 A hydrogenated castor oil 2.00 Caprylic CapricTriglycerides 45.75 A PEG-8 capric capric 3.00 glycerides A PPG-15 stearyl ether 5.00 B Adapalene 0.1 B Caprylic capricTriglycerides 4.00 C Ethanol 100 20.00 C dL alpha tocopherol 0.05 C Ascorbyl palmitate 0.1 C Hydroquinone 4.00 Specifications at TO
Macroscopic appearance: thick and supple ointment, white Microscopic aspect: Absence of hydroquinone crystals - adapalene dispersion (observed in fluorescence), crystals <2.5 to 5 μm.

Physical stability Time T + 1M T + 2M T + 3M

Conditions of stability Complies with Complies with Complies with TA specifications specifications Complies with Complies with Complies with +4 C specifications specifications Complies with Complies with Complies with 40 C specifications specifications Chemical stability (% titre relative to TO):
uz> HYDROQUINONE
Time TO T + 1M T + 2M T + 3M
Conditions of stability TA 98.2 101.6 102.85 106.9 40 C NA 100.9 105.29 104.9 uz> adapalene Time TO T + 1M T + 2M T + 3M
Conditions of stability TA 99.6 101.4 101.30 103 40 C NA 100.9 105.62 101.9 Example 3: Composition 3 Phases INCI name% form A Glyceryl behenate 16.00 A Hydrogenated beaver oil 2.00 A caprylic capric triglyceride 53.75 B Adapalene 0.1 B Caprylic capric triglyceride 4 C Ethanol 100 20.00 C DL alpha tocopherol 0.05 C Ascorbyl palmitate 0.1 C Hydroquinone 4.00 Specifications at TO
Macroscopic appearance: Thick and supple ointment, white with light reflections yellows Microscopic appearance: Absence of hydroquinone crystals, dispersion adapalene from <2.5pm to 5pm.

Physical stability Time T + 1M T + 2M T + 3M T + 6M
Conditions of stabilité1L
Compliant with Complies with Complies with Complies with TA specifications specifications specifications Compliant with Complies with Complies with Complies with +4 C specifications specifications specifications Compliant with Complies with Complies with Complies with 40 C specifications specifications specifications Chemical stability (% titre relative to TO):
* HYDROQUINONE
Time TO T + 1M + 2M T + 3M T + 6M
Conditions of stability TA 99.3 101.9 112.3 99.5 103.2 40 C NA 100.3 9.3 99.7 01.7 Oz> adapalene Time T T + 1M T + 2M T + 3M T + 6M

terms of stability TA 100.6 100.7 123.6 100 97.6 40 C NA 99.9 99.8 99.9 97.5 Example 4: Composition 4 Phases INCI name% form A Glyceryl behenate 16.00 A Hydrogenated beaver oil 2.00 A caprylic capric triglycerides 38.75 B PPG 15 stearyl ether 15.00 C Adapalene 0.1 C Caprylic capric triglycerides 4 Ethanol 100 20.00 DL alpha tocopherol 0.05 D Ascorbyl palmitate 0.1 D Hydroquinone 4.00 Specifications at TO
Macroscopic appearance: Thick and supple ointment, white with light reflections yellows Microscopic appearance: Absence of hydroquinone crystals, dispersion adapalene from <2.5pm to 5pm.

Physical stability Time T + 1M T + 2M T + 3M
Conditions of stability1 ' Complies with Complies with Complies with TA specifications specifications Complies with Complies with Complies with +4 C specifications specifications Complies with Complies with Complies with 40 C specifications specifications Chemical stability (% titre relative to TO):

* HYDROQUINONE
Time TO T + 1M T + 2M T + 3M
Condition s of stability TA 98.8 99.7 100.7 103.2 40 C NA 99.7 101.9 103.1 Oz> adapalene Time TO T + 1M T + 2M T + 3M
Condition s of stability TA 101.1 102.3 101.7 101.2 40 C NA 101.2 101 102.2 Example 5 Composition 5 Phases INCI name% form A Glyceryl behenate 16.00 Hydrogenated castor oil 2.00 Caprylic capric triglycerides 44.75 PPG 15 stearyl ether 5.00 PEG 8-Caprylic capric 3.00 triglycerides B Rucinol 5.00 Ethanol 100 20.00 DL alpha tocopherol 0.05 Ascorbyl palmitate 0.10 C Adapalene 0.10 Caprylic capric triglycerides 4.00 Specifications at TO
Macroscopic appearance: Glossy white ointment Microscopic appearance: Absence of rucinol crystals, adapalene dispersion of <2.5pm to 5pm.
Profile Haake (4s' / 20s1 / 100s1): 118/110/112 Physical stability T + 1month T + 2months Aspect TA Compliant Compliant macroscopic aux specifications specification s 40 C Compliant Compliant to the specifications specification s 4 C Compliant Compliant to the specifications specification s Aspect TA Compliant Compliant microscopic aux specifications specification s 40 C Compliant Compliant to the specifications specification s 4 C Compliant Compliant to the specifications specification s Rheology Haake 253/446/297 314/518/374 (451/2051 / 100s 1) Chemical stability (% titre relative to theoretical title):
Uz> Rucinol Time TO T + 1M T + 2M
Condition s of stability TA 102.1 101.2 100.8 40 C NA 105.2 105.4 4 C NA 104.4 99.4 Uz> adapalene Time TO T + 1M T + 2M
Condition s of stability TA 109.7 107 105.0 40 C NA 109 110.0 4 C NA 105 109.0

Claims (15)

Anhydrous pharmaceutical composition, characterized in that it comprises a) a first phenolic derivative pharmaceutical active agent chosen from hydroquinone, rucinol or lucinol and its salts, 4-hydroxyanisol, hydroquinone monoethyl ether and hydroquinone monobenzyl ether.
b) a second pharmaceutical active agent of the retinoid type, (c) glyceryl behenate, its derivatives or mixtures, d) at least one solvent of the phenolic derivative, said composition containing neither petroleum jelly nor elastomer polyorganosiloxane. 2. Composition according to claim 1, characterized in that the derivative phenol is present in an amount of from 0.01 to 10% by weight per relative to the total weight of the composition. 3. Composition according to one of claims 1 to 2, characterized in that the phenolic derivative is hydroquinone or rucinol. 4. Composition according to claim 1, characterized in that the retinoid is between 0.0001 and 1% by weight relative to the total weight of the composition. 5. Composition according to claims 1 and 4, characterized in that the retinoid is adapalene. 6. Composition according to one of claims 1 to 5, characterized in that the glyceryl behenate is present in an amount of between 1 and 40% by weight relative to the total weight of the composition. 7. Composition according to one of claims 1 to 6, characterized in that the solvent of the phenolic derivative is a solvent of alcoholic or glycolic type; 8. Composition according to one of claims 1 to 7, characterized in that what also comprises at least one lipophilic thickener and / or at least one surfactant, and / or at least one oil and / or at least one binder. 9. Composition according to one of claims 1 to 8, characterized in that the additional lipophilic thickener is chosen from oleyl alcohol, cetyl alcohol, cetearyl alcohol, stearyl alcohol, hydrogenated jojoba oil, oil of hydrogenated sunflower, hydrogenated castor oil, coconut oil hydrogenated hydrogenated lanolin oil, lanolin, glyceryl esters of acids fat, hydrogenated glycerides of coconut and diethylene glycol monostearate or propylene glycol. 10. Composition according to claim 8, characterized in that the oil is selected among vegetable oils, mineral oils, silicone oils, Caprylic / Capric Triglycerides, Octyl Dodecyl Myristate, C12-C15 alkyl benzoate, cetearyl isonananoate and mixtures thereof. 11. Composition according to one of the preceding claims, characterized in that that it comprises, by weight relative to the total weight of the composition:
at. 0.01 to 10% of at least one phenolic derivative, b. 0.0001 to 1% of at least one retinoid, vs. 1 to 40% of glyceryl behenate, d. 1 to 80% of at least one ethanolic or glycolic solvent, e. 0 to 30% additional lipophilic thickener or gelling agent, f. 0.05 to 98% fat or oil, boy Wut. 0 to 20% of additives. 12. Composition according to one of the preceding claims, characterized in that that it comprises, by weight relative to the total weight of the composition at. 0.01 to 6% hydroquinone, b. 0.001 to 0.5% of adapalene, vs. 10 to 25% of glyceryl behenate, at least 10%, d. 10 to 30% ethanol, e. 1 to 10% additional lipophilic thickener, f. 1 to 80% of oils, boy Wut. 0 to 20% of surfactants, h. 1 to 20%, binder (s), i. 0 to 10% of additives. 13. Composition according to one of claims 1 to 12, as a medicament. 14. Use of a composition according to one of claims 1 to 12 for prepare a medicament for the treatment and / or prevention of disorders hyperpigmentaires such as melasma, chloasma, lentigines, lentigo senile, vitiligo, freckles, post-hyperpigmentations Inflammatory diseases due to abrasion, burning, scarring, dermatitis, a contact allergy; nevi, deterministic hyperpigmentation genetics, hyperpigmentations of metabolic or medicinal origin, melanomas or all other hyperpigmentary lesions. 15. Process for the preparation of a composition as defined in claims 1 at 13 comprising at least the following steps:
at. Preparation of one or more non-active phases by mixing at least glyceryl behenate to the other constituents of the phase, b. Preparation of the active phase (s) by mixing a derivative phenolic and a retinoid with their respective solvent or dispersant, vs. The active phases are mixed with the non-active phase (s) in order to obtain a homogeneous composition, characterized in that the final step c) of mixing the phases is carried out at ambient temperature and that the phases are fluid in the final step c).